What cyanide is
Where cyanide is found and how it is used
Biochemical basis for poisoning
Principles of therapy
Elimination of Further Exposure
Specific antidotal therapy
Global attitude and the popular treatment
How to obtain specimens at post mortem for analytical toxicology
What cyanide is
Cyanide are the salts of hydrocyanic acid and are among the most poisonous substances known. Cyanide is rapidly acting, potentially deadly chemical that can exist in various forms. Cyanide can be a colorless gas, such as hydrogen cyanide (HCN) or cyanogens chloride (CNCL) or a crystal form that is water-soluble such as sodium cyanide (NaCN) or potassium chloride (KCN) and poorly water-soluble mercury, copper, gold, and silver cyanide salts. The most dangerous compounds are hydrogen cyanides (also known as hydrocyanic acid or prussic acid) and cyanogens, which are stored under pressure as liquid but which are used as gases, such as cyanogens chloride and bromide are gases with potent pulmonary irritant effect. Hydrocyanic acid gas is liberated from solid cyanides by the action of acids, water or even water vapor. A number of cyanide-containing compounds, known as cyanogens, may release cyanide during metabolism. Much of the cyanide used is in the form of salts, such as sodium, potassium, or calcium cyanide, but in the military cyanides are used in the volatile liquid hydrocyanic acid. Cyanide is also known by the military designations AN (for hydrogen cyanide) and CK (for cyanogens chloride). The ‘ bitter almond’ smell of hydrocyanic acid is a characteristic, but cannot be detected by some people1-3.
Where cyanide is found and how it is used
Since the days of ancient Rome, cyanide and the derivates of this highly toxic substance have been used as weapons. Nero used cherry laurel water, which contains cyanide as its principal toxic component, to poison members of his family and others who displeased him. Napoleon III proposed the use of cyanide to enhance the effectiveness of his soldiers` bayonets during the Franco-Prussian war3.
Although substances containing cyanide had been used for centuries as poisons, it was not until 1782 that cyanide itself was identified. It was first isolated from cherry laurel by the Swedish chemist Scheele, and in 1786 he was feared to be the first victim of this rapid poison in a laboratory accident. Later in 1795 Fontana investigated its mechanism of action, followed by Blakes`s attempts to antagonize its toxic effects3,4.
During World War I, in late 1915 and early 1916, the French were the only proponent for using cyanide and its derivative, hydrocyanic acid. This was made by distilling a concentrated solution of potassium cyanide with dilute sulfuric acid. Its use, however, proved to produce less than its desired effect. A highly volatile gas and lighter than air, hydrocyanic acid persisted for only a few minutes in the open air; this made it difficult to disperse a lethal concentration. The effect of cyanide were not cumulative. So these combined factor made hydrocyanic acid less effective as a weapon3.
About September 1916, the French tried another cyanide based poison, cyanogens chloride, which is heavier and less volatile than hydrocyanic acid and which had a cumulative effect on its victims. Cyanogens chloride was produced by chlorinating a saturated solution of potassium cyanide at 0ºC (32ºF). its toxicity was similar to that of hydrocyanic acid, but cyanogens chloride was more effective at low concentrations ( it irritated the eyes and lungs ). At high concentrations, cyanogens chloride is capable of killing by rapidly paralyzing the respiratory system`s nerve centre3.
At about the same time that the French launched cyanogens chloride, the Austrians introduced their own poisonous gas, which was derived from potassium cyanide and bromide. The resulting cyanogens bromide was highly volatile, nevertheless it had only a quarter of the volatile of hydrocyanic acid and was less toxic. Cyanogens bromide had a strong irritating effect on the conjunctiva and on the mucous membranes of the respiratory system. But, finally the Austrian abandoned its use. Cyanogens chloride can produce irritation of the eyes and mucous membranes similar to that produced by riot control agents3.
Hydrogen cyanide, under the name Zyklon B, was used as a genocidal agent by the German in World War II. The Nazis employed hydrocyanic acid adsorbed onto a dispersible pharmaceutical base (Zyklon B) to exterminate millions of civilians and enemy soldiers in the death camps. Zyklon B was a fumigant and rodenticide3-5.
In addition, cyanide is used by governments, terrorists , corporations, and individuals to achieve various economic, beneficial, humanitarian, or harmful ends. In 1978 near Port Kaituma, Guyana, the followers of reverend Jim Jones drank a grape-flavored drink mixed with cyanide, and more than 900 children and adult members of the People`s temple committed mass suicide3.
Reports have indicated that during the Iran-Iraq War in the 1980s, hydrogen cyanide gas may have been used in addition to other chemical agents against the inhabitants of the Kurdish city of Halabja in northern Iraq and the inhabitants of the Syrian city of Hama and possibly in Shahabad, Iran. Based on this recent history, acute cyanide poisoning continues to constitute a threat for U.S. soldiers in future conventional or non conventional conflicts3,6.
Cyanide is the agent used in “gas chambers” in which a cyanide salt is dropped into an acid to produce HCN. These chemicals –an acid and a cyanide salt- were found in several subway restrooms in Tokyo, Japan, in March 19953.
The cyanide have no therapeutic value, but in manufacturing, cyanide is used to make paper, textiles, and plastics. It is present in the chemicals used to develop photographs. Cyanide salts are used in metallurgy in a number of chemical processes, including electroplating, case hardening of iron and steel metal cleaning, and removing gold from its ore. Cyanide gas is used as a fumigating agent to exterminate other animal pests and insect in ships and buildings1,3,6-7.
Certain rare plants containing cyanide include apricot pits, wild cherry, peach, plum pits, corn (sorghum), chickpeas, cashew, chickpeas, some other fruits and vegetables contain cyanogenic (i.e., cyanide-forming) glycosides (such as amygdalin) that release hydrogen cyanide when chewed or digested. A type of potato called cassava contains cyanide too. Cassava is a staple in several tropical countries and is blamed for the high incidence of tropical ataxic neuropathy in these areas1,3,6,,8 . Beside that cyanide can be produced by certain bacteria, fungi, and algae. In the body, cyanide combines with chemical to form Vitamin B128. Cyanides are present at low concentrations in several naturally occurring environmental sources, it is not surprising that most animals have intrinsic biochemical pathways for detoxification of the cyanide ion7.
The supposed cancer-fighting substance called laetrile (made from apricot pits) used to be sold to desperate cancer patients as a cancer chemotherapeutic, have been responsible of the death of some patients who took this substance3,4,7.
Certain chemicals, after ingestion, can be changed by the body into cyanide. Most of these chemicals have been removed from the market, but some old artificial nail polish remover or chemicals found in acetonitrile-base products, solvents and plastics manufacturing solutions can contain these substances,7,9,10 . In 1989, the food and Drug Administration quarantined all fruit imported from Chile after traces of cyanide were found in 2 Chilean grapes9.
Combustion of synthetic product that contains carbon and nitrogen, such as pyrolysis of plastic and nitrile-based polymer fibers (synthetic fibers) can create cyanide fumes. Cigarette smoke contains cyanide; the nonsmoker averages 0.06 µg /mL of cyanide in blood, whereas the smoker has 0.17 µg/mL. The effects of cyanide and of carbon monoxide, also formed in fires, they both contribute to tissue hypoxia by different mechanisms. The two gases are major causes of combustion-related fatalities. In residential fires, cyanide poisoning may be more significant than has previously been esteemed. The short half-life of cyanide in blood contributes to the low concentration of cyanide found in fire victims when blood is checked after victims reach the hospital3.
From April 1988 to April 1989, a team of French investigators collected samples-on the scene-from 109 victims of residential fire in and around Paris, France. The data they gathered were compared with data from a control group (N=114) of individuals whose injuries were not caused by fire.
Blood cyanide concentrations were much higher in the fire victim than in the control group (Table 2 ) and victim who died had significantly higher levels ( > 5-fold) than victim who survived. Contrary to what previous researchers have concluded that cyanide may a few substances in contributing cause of death. Even it can be said that many deaths to cyanide poisoning is a mistakes, but the result from this study “suggest that cyanide poisoning may more predominant factors than carbon monoxide poisoning as the caused of death in some fire victims3,5,9.
Biochemical basis for poisoning
The toxic effect of cyanide is ascribed predominantly to the production of anoxia following inhibition of cytochrome oxidase, a terminal mitochondrial respiratory chain enzyme. This enzyme contains two heme A and two copper ions. Cyanide has a special affinity for the heme ion and the reaction of cyanide with the multimeric iron enzyme complex is facilitated by first penetration of cyanide to protein crevices, with initial binding of cyanide to the protein followed by binding of cyanide to heme ion. Thereby, a cyanide-heme cytochrome oxidase complex is formed which renders the enzyme incapable of utilizing the oxygen. The resultant oxygen saturation of the blood imparts a cherry red color, which aids the diagnoses in most instances of cyanide poisoning. Inhibition of cytochrome oxidase results in interruption of electron transport chain and the oxidative phosphorylation. Resultant anaerobic metabolism with severely decreased ATP generation and concomitant increase in lactic acid production eventually leads to tissue hypoxia and metabolic acidosis. The inhibitory properties of cyanide may be ascribed to its ability to complex with metals. Besides, iron containing cytochrome oxidase, there are other metallo-enzymes containing molybdenum, zinc or copper which are equally sensitive to cyanide. Other mechanism for cyanide inhibition may be attributed to its affinity to Schiff base intermediates, e.g. ribulose diphosphate carboxylase and 2 – keto – 4 – hydroxyl glutarate aldolase involving formation of a cyanohydrin intermediate. Therefore, cyanide toxicity may not be attributed solely to a single biochemical lesion but a complex phenomenon3,4,7.
Perhaps of greatest importance is the formation of cyanomethemoglobin (CNMetHB), which is produced when the cyanide ion (CN-) react with MetHb. Methemoglobin is formed when hemoglobin (Hb) react with a variety of oxidants (eg, nitrite, dimethylaminopheno[DMAP], and ρ-aminopropiophenone [PAPP]. Cyanide may complex with endothelial-derived relaxing factor (EDRF, which is thought to be nitric oxide). Cyanide can interfere with the action of carbonic anhydrase and lower pH. Finally, albumin can exhibit enzymlike behavior and use bound elemental sulfur to detoxify cyanide. It is also theoretically possible to prevent entrance of cyanide ions into the cell by blocking transport mechanisms with substances such as DIDS3.
Intercellular enzymes may be involved for cyanide detoxification. The generalized reactions of rhodanase, mercaptopyruvate sulfurtransferase, thiosulfate reductase, and cysthathionase shown within the cell. The most important route of cyanide excretion is by formation of thiocyanate (SCN-), which is subsequently excreted in the urine. Thiocyanante possesses a less inherent toxicological hazard than cyanide, cyanate, or isocyanate. Thiocyanate formation is catalyzed directly by the enzyme rhodanase and indirectly via a spontaneous reaction between cyanide and the persulfide sulfur product of the enzyme 3-mercaptopyruvate sulfurtransferase and thiosulfate reductase. The mechanisms of all three enzymes as well as the pharmacokinetics of thiocyanate formation have been studied. Although 3-mercaptopyruvate functions to convert cyanide to this cyanate , it is instability and sulf-auto-oxidation at a basic pH may mask this effect. The enzymatic routes are efficient but have an insufficient capacity for detoxification in acute poisoning because of lack of sulfur donors. The mitochondrial sulfurtransferase reactions are exploited by the administration of sodium thiosulfate in the treatment of acute poisoning. It is still not known with any certainty, however, what specific endogenous sulfur sources participate in the formation of thiocyanate from cyanide3,4,7.
A minor route of metabolism is the oxidation of cyanide to cyanate (CNO-), which occur via enzymatic and nonenzymatic pathways. The interaction of cystine and cyanide to form 2-amino thiazoline 4-carboxylic acid and its tautomer accounts for approximately 20% of cyanide metabolism. However, the protection conferred by forming cyanate derivatives is limited because of the cell`s inability to utilize oxygen during cyanide intoxication. It is still controversial that hyperbaric oxygen or perhaps oxygen itself can reduce cyanide toxicity by competing with cyanide at some site (such as cytochrome oxidase in the mitochondria, which is thought to be a primary site for cyanide poisoning)
Combined, these metabolic routes detoxify 0.017mg of cyanide per kilogram of body weight per minute in the average human. Cyanide is one of the few chemical agents that does not follow Haber`s law, which states that the Ct (the product of concentration and time) necessary to cause to cause a given biological effect is constant over a range of concentration and times. For this reason, the LCt 50 (the vapor or aerosol exposure that is lethal to 50% of the exposed population) for a short exposure to a high concentration is different from a long exposure to a low concentration3.
It is not easy to determine what are the lethal doses of cyanide to man. Human cyanide poisoning is associated with a mortality rate of 95 %. Taken orally the fatal dose of HCN to adult is estimated at 50-100 mg, and for potassium cyanide (KCN) , about 150-250 mg. However, victims ingesting as much as 3 g of KCN have been saved with immediate therapy. Inhalation of HCN at a concentration of 270 ppm (approximately 0.3 mg HCN per liter) will be immediately fatal. Victims having a blood cyanide level of 2.5-3.0 µg/ml frequently succumb to respiratory cessation within 20-30 min of exposure or may survive even up to 3 hr4.
Although they are generally considered to be very toxic substances, when compared with other lethal chemical warfare agents, cyanides are among the least toxic. Even in closed room with the introduction of pure gaseous cyanide in high concentrations, as occurred in the Nazi death chambers, death did not occur and was not immediate for a number of minutes3,5. The LCt50 for hydrogen cyanide (hydrocyanic acid) is generally stated to be 2,500-5,000 mg•min/m3; for cyanogen chloride, about 11,000 mg•min/m3. (comparable values for the nerve agents are 10-200 mg•min/m3; for sulfur mustard, 1,500 mg•min/m3; and for phosgene, 3,000 mg•min/m3)3.
The toxicodynamic effect can vary depending on the dose, route and time of exposure, speed of administration, chemical form of the cyanide, and other factors including the gender, age, weight, stress level, and general physical condition of the recipient3,10.
The estimated intravenous dose that is lethal to 50% of the exposed population (LD50) of hydrogen cyanide for man is 1.0 mg/kg, and the estimated LD50 for liquid on the skin is about 100 mg/kg3.
Cyanide induces fatality in seconds to minutes following inhalation or intravenous injection, in minutes following ingestion of soluble salts, or in minutes following ingestion of soluble salts, or minutes (hydrogen cyanide) to several hours (cyanogens) after skin absorption1.
Suicide by cyanide poisoning occurs predominantly in males, as does industrial exposure. And deliberate ingestion of cyanide occurs mostly in adults. Poisoning is enhanced by an empty stomach and high gastric acidity. A full stomach may delay symptoms for up to 4 hours. Smoke inhalation affect all ages. Chronic cyanide poisoning affects children and adults1. The measurement of blood levels has little clinical significance but may be of forensic importance3. Generally, serum levels greater than 1 mg/liter are fatal. Smokers may have incidental serum cyanide levels of 0.1 mg/liter1,3.
The clinical manifestation of acute cyanide poisoning varies in both time and intensity depending upon the magnitude of exposure3,4,10. Hydrocyanic acid is absorbed from any mucous surface and enters the system just as easily by way of the nose and throat as by the stomach10. Various non-specific signs and symptoms like headache, dizziness, nausea, vomiting, confusion, coma and incontinence of faeces and urine occur. Physiologically a series of events like dyspnoea, incoordination of movement, cardiac irregularities, convulsive seizures, coma and respiratory failure may occur leading to death. These signs are not specific for cyanide poisoning, which makes the distinction from other types of poisoning very difficulties without a history of exposure3,4.
On a military battlefield, casualties will be from exposure to cyanide gas; this can be fatal within minutes after exposure to high concentrations. An initial hypercapnea (15 sec after exposure), due to the effect of cyanide on the chemoreceptor bodies, is closely followed by a loss of consciousness (30 sec after exposure). This progress to apnea (3-5 min after exposure), cessation of cardiac activity (5-8 min after exposure), and death3.
After exposure to lower concentrations, or exposure to lethal amounts via the oral or percutaneous routes, the effects are slower to develop. Foe example, after ingestion of a lethal dose of a cyanide salt, the casualty might have 15 to 30 minutes of survival time during which an antidote could be administrated1,3,4,7,9.
Because the toxic effect of cyanide is to block tissue uptake and utilization of oxygen, the casualty is transiently flushed and may have other, related signs of poor tissue oxygen extraction. For example, funduscopic examination shows an equally bright red color for retinal arteries and veins because of venous blood is also responsible foe a “cherry-red” skin color, but this sign may not always be present3.
Relevant laboratory findings include an early decreased arteriovenous different in the partial pressure of oxygen (Po2) with progressive lactic acidosis3.
Timely measurements of blood and urine concentrations for suspected intoxicants are useful in guiding clinical therapy, especially, when there is toxicity associated with the treatment agents. Unfortunately, analysis of cyanide in biological fluids is a difficult task for a variety of reasons. Also, measurements of blood cyanide concentrations are almost never available during the treatment phase. Blood concentrations of cyanide and associated clinical effects are shown in the table 3.
Documentation of blood cyanide levels is useful in confirming the clinical diagnosis and in subsequent follow up investigation. The red blood cells contain most of the cyanide in the blood, so an assay of the whole blood is necessary. Furthermore, cyanide levels tend to fall in stored samples because of the compound`s short half-life, and this process can only partially be limited by optimal storage conditions. Therefore, the time of sampling and the conditions of storage are very important factors to consider and record.
Principles of therapy
An understanding of the toxicology and pathophysiology of cyanide poisoning leads directly to the principles of therapy : eliminate further exposure, and institute supportive and specific antidotal therapy.
Elimination of Further Exposure
The first principle of therapy is the obvious one : eliminate any potential source of continuing cyanide poisoning :
Remove the patient from an environment containing cyanide.
Remove all contaminated clothing; rinse skin with soap and water alone if there is liquid on the skin. If cyanide contacts eyes, immediately irrigate with water for at least ten minutes. (Richard eliot HSE)
Lavage if cyanide has been swallowed. And do not give anything by mouth. Treat patient as for inhalation. (Richard eliot HSE)
Possibly the most important elements of therapy are general supportive actions, which, by themselves, can effect the recovery of most casualties without further risk from specific antidotal therapy. There are probably the only indicated therapies for casualties of cyanide poisoning who arrive conscious at the emergency medical treatment situation.
For correcting of the anoxia : 100% OXYGEN therapy immediately; duration : 3 hours ; after improvement 50% oxygen for 3 hours and 30 % oxygen for 24 hours (endotracheal intubation if necessary) hyperbaric oxygen can be used when CNS does not improve with traditional treatment. The use of hyperbaric oxygen in cyanide intoxication is still controversial. Supplemental oxygen with or without assisted ventilation clearly augment the effect of specific antidotes in animal studies; however, despite encouraging reports, there is inconclusive evidence of further benefit from the use of hyperbaric oxygen3,4. Artificial respiration, mouth to mouth resuscitation should be avoided because has risk of self poisoning ; cyanide products are eliminated unchanged by the lung1,7,10.
Lactic acidosis resulting from anaerob metabolism should be treated by intravenous administration of sodium bicarbonat 1 milliequivalent /Kg; further administration will be based on arterial blood gas determinations. Seizures controlled by the administration of anticonvulsants such as diazepam. Because correction of deficiencies in tissue perfusion and oxygenation is the ultimate goal of supportive therapy and is also important for the success of specific antidotal therapy, it is critically important to maintain an effective cardiac rhythm; this can be accomplished with cardiopulmonary resuscitation, if necessary, in the early stages of treatment.
Specific antidotal therapy
A wide variety of compounds have been used as cyanide antidotes and they have been classified into four major groups based on their mechanism of action; Their mechanism of action, efficacy and toxicity have been reviewed as part of a joint IPCS (UNEP,ILO,WHO)/CEC project to evaluate antidotes used in the treatment of cyanide poisoning.
other methemoglobin formers
Cobalt containing compounds
Dicobalt edetate (Kelocyanor)
Hydroxocobalamin (Vitamin B12 a)
Other cobalt compounds
These are compounds that inactive cyanide by binding it or by forming methaemoglobinemia, which in turn sequesters cyanide.
The basic aim of rapid detoxification of cyanide is prevention or reversal of inhibition of cytochrome oxidase by cyanide. This is usually accomplished by providing a large pool of ferric iron in the form of methemoglobin to complex cyanide. Cyanide preferentially competes with the Fe+++ of methemoglobin as compared to that of cytochrome oxidase, and eventually blinds with the former to form cyanmethemoglobin. Methemoglobin removes cyanide from extracellular fluid space and, by doing so, displaces cyanide from the intracellular fluid. Thereby, the activity of inhibited cytochrome oxidase is restored.
Methemoglobin formation, both sodium and amyl nitrite cause significant vasodilatation, which warrants careful monitoring. Marked vasodilatation with orthostatic hypotension, dizziness, and headache, in addition to the unpredictable levels of methemoglobin formed, limit the utility of amyl nitrite in an upright casualty. Therefore, if casualty is conscious and able to stand, he should not receive any nitrite. These factor, together with other concerns, have caused amyl nitrite to be removed from the cyanide antidote kit in the U.S Army formulary for field units.
Some data indicate that nitrites exert their action by mechanism other than methemoglobin formation. It has been suggested that the protective effect is due to the vasodilating effect of nitrite. Several α-adrenergic antagonists (eg.chlorpromazine, promethazine, promazine, and phenoxybenzamine) that cause vasodilatation also antagonize cyanide toxicity. Further information is needed to determine the mechanism or mechanisms by which chlorpromazine and phenoxybenzamine reverse cyanide intoxication.
Inhalation of amyl nitrite as a first aid measure to cyanide poisoning is known for many years. However, the efficacy of amyl nitrite as methemoglobin inducer remained disputed on account of its inability to generate methemoglobin greater than 6 %, while about 15 % is required to challenge one LD50 dose of cyanide. Now the protective effect of amyl nitrite is attributed to its vasodilatory effect than can reserve the the early cyanide induced vasoconstriction. Artificial ventilation with amyl nitrite broken into ambu bags has been reported as a life saving therapy in cyanide poisoned dogs, prior to introduction of significant level of methemoglobulinemia.
Sodium nitrite (SN) is the most prevalent drug of choice for cyanide poisoning. When given intravenously (i.v.) it takes about 12 minutes to generate approximately 40 % of methemoglobin. In spite of this delay in inducing a significant level of methemoglobulinemmia, a reasonable protection offered by SN can be ascribe to its vasodilatory property. A serious problem with SN is that i.v. administration may be accompanied by serious cardiovascular difficulties, particularly in children, for whom an adjusted dose is recommended. Since SN induced methemoglobulinemia impairs oxygen transport, it can not recommended for fire victims where in most instances HCN exposure is accompanied by carbon monoxide poisoning. Since carbon monoxide also impairs oxygen carrying capacity of blood, administration of SN would further aggravate the hypoxic condition. Alternative therapy in this situation consists of administering oxygen, thiosulfate, and other standard supportive measures. SN is also not advised for individual with glucose-6-phosphatasse dehydrogenase (G6PD) deficient red cells because of possibility of serious hemolytic reactions.
Sodium nitrite is available in 10-mL ampules containing 300 mg mg for intravenous administration. The solution of sodium nitrite (30 mg/mL) should be given to an adult intravenously over 5 to 15 minutes, with careful monitoring of blood pressure. A single dose is sufficient to rise the methemoglobin level to 20 % in an adult, and a second dose, up to half as large as the initial one, can be given. Methemoglobin levels should be monitored if possible and kept bellow 35% to 40%, the range that is associated with oxygen-carrying deficits caused by methemoglobin itself. Because most automated clinical analyzers do not detect cyanmethemoglobin, the residual normal hemoglobin capable of oxygen transport can be overestimated by measuring total hemoglobin only.
In children, sodium nitrate can cause lethal methemoglobin levels if the dose is too high. The recommended dose for children is 0.33 mL of the 10% solution per kilogram of body weight.
The relatively slow rate of methemoglobin formation by SN prompted the development of rapid methemoglobin formers like amoniphenols. 4-dimethylaminophenol (DMAP) is the treatment of choice for cyanide poisoning in Germany. A dose of 3.25 mg/kg.,i.v. of DMAP was reported to produce methemoglobin level of 30% within 10 min and 15% methemoglobinemia was attained within one minute without any immediate effect on cardiovascular system. However, there are differences in individual susceptibility to DMAP which may result in an undesirable levels of methemoglobulinemia even after normal therapeutic doses. Intramuscular injection of DMAP results in local abscess and fever. Its clinical application remains limited on account of its other toxicological implication like nephrotoxicity. Co-administrator of a reduced dose of rapid methemoglobin inducer like DMAP and a slow inducer like SN were also found to be an effective pretreatment against acute cyanide poisoning.
Other methemoglobin formers :
Hydroxylamine (HA) was yet another rapid methemoglobin inducer that was endowed with an anticonvulsive property. In view of cyanide induced convulsions and the toxicity of DMAP, the efficacy of HA co-administration with SN was so examined in rats. Although, this regiment minimized the cyanide induced convulsions, it was less effective as compared to SN+DMAP treatment. In addition to prophylaxis, co-administration of SN and DMAP or HA were also effective therapeutically, but their extrapolation to humans needed caution in view of the persistent toxicity of these regimens.
Another group of methemoglobin formers namely aminophenones and derivates PAPP (p-aminopropiophenone), PAOP (p-aminooctanoylphenone), PNPP (p-nitrosopropiophenone) and PHAPP ( p-hydroxy aminopropiophenon ), out of all these agents PPAP was the most effective as prophylaxis. Another alternative treatment of cyanide poisoning, involve stroma free methemoglobin solution (SFMS) was proposed by Ten Eyck et al . intravenous administration this solution did not impair the oxygen carrying capacity of blood as caused by most other methemoglobin formers and directly sequestered cyanide to protect a 4 X LD50 dose of sodium cyanide in rats.
Cobalt containing compounds
Cobalt ion which forms a stable metal complex with cyanide is as effective therapeutic agent against cyanide poisoning.
Dicobalt edentate (Kelocyanor)
Cobalt salts have been shown to be an effective means for binding cyanide in vitro and in vivo. Kelocyanor, the cobalt salt of ethylene diamine tetra acetic acid (EDTA), which is commercially available in Europe but not in the United States, is administrated intravenously. In comparison studies against nitrite and thiosulphate , the cobalt chelate was thought to be superior; however, in other studies the nitrite-thiosulfate combination was found to be superior.
This agent (300 mg of dicobolt edentate in glucose solution;i.v.) is the current treatment of choice in France and United Kingdom. The drawback of cobalt compounds is their rather severe toxicity. Cardiac effect such as angina pectoris and ventricular arrythmias, edema around the eyes, vomiting, and death have been observed. A clinical caveat is that severe toxicity from cobalt can be seen even after initial recovery from acute cyanide poisoning.
Hydroxocobalamin (Vitamin B12 a) :
This agent is perhaps the most promising cyanide antidote used in human toxicology. With the exchange of hydroxyl group of hydroxycobalamin for cyanide, non toxic cyanocobalamin (Vitamin B12) is formed. However, use of this antidote remained limited on account of the large dose required to challenge cyanide poisoning. An injectable solution of hydroxocobalamin (5 g in water) is now available in France and Germany. In France a 4g hydroxocobalamin solution in 80 ml of sodium thiosulphate (STS) has also developed. Recorded side effects of hydroxocobalamin includes anaphylactoid reactions and acne.
Other cobalt compounds
Cobaltous chloride, cobaltous acetate, cobalt histidine and sodium cobalt nitrite are also reported to antagonize cyanide poisoning. However, none of them has been used clinically.
Cyanide is a nucleophile known to react with various carboxyl moieties like ketones and aldehydes to give cyanohydrine derivatives. Sodium pyruvate was reported to effectively challenge acute cyanide poisoning in mice. Another α-ketoglutaric acid (α-KG) is currently being pursued widely as a cyanide antidote. Protective effect of α-KG was also observed against cyanide induced convulsions in mice. Α-KG either alone or in combination with SN and/or STS attenuated toxicity in mice exposed to cyanide through different routes. Prophylactic or therapeutic ability of α-KG was also shown to be augmented by oxygen. Cyanide induced histotoxic hypoxia was reversed by α-KG which was found to be more effective than cobalt edetate and sodium pyruvate. Although, clinical trials of this agent as cyanide antidote has not yet been conducted in humans, based on the promising results in experimental animals, it is presently envisaged as a potential antidote for cyanide poisoning. It is considered safe as oral form of α-KG is sold as an over-the counter nutritional supplement (Klaire Laboratories, San Marcos, CA)
Under this group those agents are listed which enzymatically detoxify cyanide by converting it to a relatively non-toxic product which is readily eliminated from the body. The reaction can be catalyzed by augmenting the levels of the enzyme exogenously or by supplementing the enzyme exogenously or, by providing more substrate to the enzyme, which in this case are sulfur donors. The major mechanism of removing cyanide from the body is its enzymatic conversion by the mitochondrial enzyme rhodanase (thiosulphate-cyanide sulphur transferase,) to thiocyanate. Transulfuration of cyanide is also facilitated by β-mercaptopyruvate-cyanide sulfur transferase. The enzymatic conversion of cyanide to thiocyanate requires a source of sulfane sulfur (a divalent ionized sulfur bound to another sulfur atom) which is usually offered by thiosulfates or other biological compounds containing sulfane sulfur, like polythionates, thiosulfonates, persulfides etc.
It is presumed that the sulfane sulfur binds first to the serum albumin to yield sulfane sulfur albumin complex which eventually reacts with cyanide to form thiocyanate. Exogenously administrated thiosulfate usually in the form of STS would supplement this reaction rapidly. STS alone administrated i.v. may be sufficient in moderate cases of cyanide poisoning while severe cases of poisoning may necessitate co-administration of other antidotes, preferably SN. STS is contra-indicated in patients with renal insufficiency as the thiocyanate formed may cause toxicity. Endogenous augmentation of rhodanase has not been worked out extensively but exogenous supplementation has been reported to accelerate the transulfuration of cyanide to thiocyanate. However, stability and sensitivity of the enzyme remains to be addressed.
Oxygen appears to be a physiological antagonist. Oxygen alone at hyperbaric pressure has slight protective effect in cyanide poisoning but it dramatically potentiates mechanism is not yet clear because inhibition of cytochrome oxidase by cyanide does not deplete the availability of oxygen, only cellular utilization of oxygen is impaired. It is presumed that intracellular oxygen tension may be high enough to cause non enzymatic oxidation of reduced cytochrome or oxygen may displace cyanide from cytochrome oxidase by mass action. During transulfuration there is accumulation of sulphite (SO3-2) which inhibits the progress of the reaction. It is proposed that oxygen accelerates the oxidation of sulfite, thereby enhancing cyanide detoxification.
The compounds classified as biochemical antidotes have largely unexplained mechanism of action and are also regarded as non-specific antidotes. These compounds are usually not very effective per se but as adjuncts significantly augment the efficacy of conventional antidotes. A few chemicals belonging to this class of antidotes :
The potent vasodilatory action of nitrites prompted the examination of vasogenic drugs as cyanide antagonist. Chlorpromazine a neuroleptic phenothiazine, was found to significantly potential the efficacy of SN and STS combination in cyanide toxicity. Its protective effect was attributed to its α-adrenergic blocking property. Subsequently, the antidotal activity of chlorpromazine was related to its ability to sustain cellular calcium hemostasis and maintenance of membrane integrity by preventing peroxidation of membrane lipids.
Other α-adrenergic blocking agents like phenoxybenzamine and various autonomic drugs, vasodilators such as papaverine, organic nitrates and anti-histaminic compounds have shown some antidotal efficacy in cyanide poisoning. Cyanide induces respiratory cessation mediated through inhibitory action of released endorphin. Therefore, stereo-specific opiate antagonist cyanide induced lethally in mice. Role of neuronal calcium in cyanide induced neurotoxicity and beneficial effects of chlorpromazine and calcium channel blocker (diltiazem) are also well documented. The recent thrust to develop mechanistic based antidotes against cyanide poisoning has identified some new classes of lead compounds like calcium antagonist, non-hypnotic barbiturates, anticonvulsants, adrenergic blockers, antipsychotics, nitric oxide generators, other neuroprotective drugs, antioxidant, plasma expanders, glycolytic substrate, carbonyl compounds etc. Many of these drugs have not been used clinically but their results in experimental animals or in vitro are quite encouraging.
Global attitude and the popular treatment
A retrospective examination of various cyanide antidotes reveals that there is no unanimity of opinion regarding the efficacy of a particular treatment regiment. The recommended agents or components of specific antidotal therapies for cyanide poisoning vary according to country and medical custom. This diversity seems to be based, in part, on where the drugs were initially developed, used and due to different experimental conditions, test protocols and species of animals employed in evaluating various antidotes3,4. The aims of the recommended therapies are generally similar, however, in that one drug is given for immediate relief from histotoxic effect of cyanide complexed with cytochrome oxidase3,4,7. There is no global unanimity on this issue, like SN and STS combination is the drug of choice for cyanide poisoning in U.S.A. and many other countries, France and U.K. have adopted kelocyanor while Germany is still continuing with DMAP and STS combination. However, SN (10 ml of 3 % solution) and STS (50 ml 25% solution) combination is still the most prevalent treatment in cyanide poisoning. Artificial ventilation with 100 % oxygen via ambu bag containing the contents of two ampoules of amylnitrite (0.6 ml) is usually practiced as the first aid therapy. The use of antidote should be restricted to patients in deep coma with respiratory insufficiency. Supportive therapy of diazepam i.v.(3 x 10 mg) and 4.2% sodium bicarbonate solution to correct the convulsions and metabolic acidosis respectively have also been used in human poisoning. To revert excessive methaemoglobulinemia i.v. administration of 30 ml of 1 % methylene blue solution is also recommended.
Externally there can be wide variations in the appearance. Traditionally, the hypostasis is said to be brick-red, due to excess oxyhaemoglobin (because the tissue are prevented from using oxygen) and to the presence of cyanmethaemoglobin. Many descriptions refer to a dark pink or even bright red skin, especially in the dependent areas, which can be confused with carboxyhaemoglobin. The few cases seen by the author have shown a marked dark cyanotic hypostasis, perhaps caused by lack of oxygenation of the red cells by paralysis of the respiratory muscle. There may be no other external signs apart from the color of the skin and possibly black vomit around the lips11.
There may be a smell of cyanide about the body, and a distinct odor of bitter almonds about the viscera especially in the skull cavity and the brain10. Though it is well known that many persons cannot detect this, so the telltale odor of bitter almonds cannot be used as a guide because 40% to 60% of the population is unable to dettect cyanide by smell. The ability being a sex-linked genetic trait1-13.
This may be of importance to pathologists and mortuary staff, as corpes dead of cyanide poisoning can present a health hazard. Reported that a pathologist became ill and was temporarily disabled shortly after conducting an autopsy on a suicide who has swallowed a massive amount of potassium cyanide. Presumably he had inhaled hydrogen cyanide from the stomach contents when examining the viscera11.
The materials usually saved for toxicologic examination are the stomach contents, lungs, brain and visceral organ like the liver. If the poison is inhaled, the lung will show a high hydrocyanic acid content than the stomach contents. If poison is ingested most of it will be in the stomach, and the lungs will giv only a small amount3,10.
Cyanide concentrations in tissue, such as liver, lung, spleen, and heart, may be more accurate indicators of the blood cyanide intoxication levels3. cyanide appears to display first-order kinetics during the period of initial toxicity. The volume of distribution for cyanide appears to change as the blood levels of the chemical change, but these alteration probably reflect the marked intracellular sequestration of the molecule. Ingestion of cyanide results in much higher levels in the liver than does inhalation; this is useful differential point in forensic investigation3.
Internally the tissues may also be bright pink caused by the oxyhaemoglobin that cannot be utilized by the tissues – which is probably more common than the presence of cyanmethaemoglobin.
The stomach lining may be badly damaged and can present a blackened, eroded surface, by altered blood staining the stripped mucosa. This is mainly because of the strongly alkaline nature of the hydrolyzed sodium or potassium salts of cyanide; hydrogen cyanide itself causes no such damage. The findings at autopsy are otherwise the same as described above under hydrocyanic acid10,11. In less severe cases, the stomach lining will be streaked with dark red striae, where the rugae have been eroded while leaving the interlining folds relatively unharmed. The stomach may contain frank or altered blood from the erosions and haemorrhages in the walls. If the cyanide was in dilute solution, there may be little damage to the stomach, apart from pinkness of the mucosa and perhaps some petechial haemorrhages. There may also be un dissolved white crystals or powder, with the almond-like smell of cyanide mentioned above10,11.
As death usually rapid, little of the contents will have passed into the intestine. The oesophagus may be damage, especially the mucosa of the lower third, though some of this may be a post mortem change from regurgitation of the stomach contents through the relaxed cardiac sphincter after death. The other organs show no specific changes and the diagnosis is made by history, smell and the reddish color of the internal tissues, and often skin.
The detection and quantitation of cyanide in the blood after decomposition is difficult. Cyanide may be produced postmortem in a body or even in a test tube, due to decomposition. In addition, if the method of analysis is not absolutely specific, other substances in the blood (sulfides) may react like cyanide, giving falsely elevated levels of cyanide5.
Pathologically no particular lesions can delineate that the lesions are principally in the central nervous system, predominantly necrosis in the white matter. Probably the most wide-spread pathologic condition attributed to chronic cyanide poisoning is tropic ataxic neuropathy following cassava consumption4 .
Case report12 : (because the small number of victims in autopsy room at forensic department University of Indonesia, this case I downloaded from cyanide poisoning on net )
A male, 20-year-old university student, studying Chemistry. He shouted from his lodging's window that he had been poisoned, and was found in a collapsed state in his bedroom. He died two hours later in hospital At post mortem, six hours later, there was a distinct smell of almonds associated with the body. The organs of the body were congested and the stomach contents smelt strongly of almonds.The mucosa of the stomach was noted to be blue, with heavy staining of the fundus and body of the stomach, but the antrum was spared. Sometime later, a bottle with a small quantity of residual liquid was found on the premises. Toxicological analysis identified an aqueous solution of 13% sodium nitroprusside. Death was caused by cyanide poisoning. Nitroprusside contains five cyanide groups (CN) and one nitrous oxide group (NO). The latter component accounts for its therapeutic action as an antihypertensive agent. Nitroprusside in the blood reacts rapidly with haemoglobin to produce thiocyanate and cyanide, through which its toxic effects are exerted.
The reaction seen in the stomach will be familiar to all histopathologists, as it is the basis of Perl's Prussian blue reaction. In histological sections, ferric iron in the form of ferric hydroxide (Fe(OH)3)) is unmasked from compounds such as haemosiderin by acid. The ferric iron then reacts with a ferrocyanide (nitroprusside) to produce an insoluble blue compound, ferric ferrocyanide. The exact source of the ferric ions in the stomach mucosa is unknown (possibly altered blood). Antral sparing from coloration occurs as a result of its relative lack of acid secreting cells. Histology of the mucosa showed autolysis, and the positioning of the blue staining was difficult to assess, although most staining appeared to be superficial.
Interestingly, the first person to find the victim did not smell the typical "bitter almond" scent of cyanide. Ballantyne reported that the typical smell of cyanide was not present in the tissues of cadavers victim to this poison. However, this study used a single pathologist1. Certain individuals cannot detect the smell of cyanide and, anecdotally, 1 in 6 people are not capable of identifying its odor. Cyanide anosmia appears to be more prevalent in males, although its exact genetic basis is not fully understood.
The case was reported in 1931 in the British Medical Journal (1931, ii, 344) by Professor Fowweather, and is part of the collection at the University of Sheffield's Department of Forensic Pathology.
How to obtain specimens at post mortem for analytical toxicology
After the body death, body fluids and tissues can be rapid changes in cellular biochemistry as autolysis proceeds, and drugs and other poisons may be released from their binding sites in tissues and major organs, also unabsorbed drug may diffuse from the stomach. Special care should always be taken in the selection of blood and tissue sampling site(s), the method of collection of samples, and the labelling of sample containers.
The standard procedure for toxicological analysis performed at laboratory requires the collection of blood and urine samples. Appropriate tissue (brain, liver etc.) and stomach contents should be collected at post-mortem but will not normally be required unless special investigations are required; however they should be retained at the mortuary. Special care is required in specimen collection and storage for certain drugs and poisons e.g. alcohol, cocaine, insulin, solvents, gases and cyanide. The amount found on analysis naturally depends on the amount taken and the time between administration and death. Though the latter is usually measured in minutes, low dosage-or treatment- may allow survival for hours or even days.
In suspected cyanide poisoning it is helpful to collect specimens of blood from more than one peripheral site, and also stomach contents. In cases where the source of cyanide is not known it may be useful to obtain a small specimen of brain (~ 20 grams) from a site deep within the brain to confirm the presence of cyanide.
If there is prolonged storage of blood specimens after post-mortem, it is possible to generate significant quantities of cyanide, probably as a product of bacterial action. The use of blood specimen containers containing 2% sodium fluoride is recommended to prevent this. Blood and tissue specimens are best stored at 4oC and should be analysed as soon a possible after collection. It is important to try to identify the exact source of the cyanide taken by the deceased.
Measurement of both carbon monoxide and cyanide may be helpful in cases involving fires. However, analysis of blood specimens should be carried out without delay. In such cases there is a tendency for the carbon monoxide concentration to decrease with time and the cyanide concentration to increase. Use of blood specimen containers containing 2% sodium fluoride is advisable, particularly in "sensitive" cases or those involving multiple fatalities.
Urine (preferably at least 20 mL) should be placed in 1-2 plain 20 mL sterile plastic container(s). If only a small amount of urine is available, this should be placed in a plain 5 ml glass tube. Boric acid containers should NOT be used. Urine specimens, however small, taken at post-mortem are of great value in screening for an unknown drug or poison, particularly substances of abuse.
Blood for quantitative analysis (~ 5 mL) should be taken from two distinct peripheral sites, preferably left and right femoral veins, with care taken not to draw a large volume containing blood from more central vessels. The precise sampling site must be indicated on the label. Femoral blood can be taken by cutting the external iliac vein proximal to the inguinal ligament, and milking the distal cut into a plain 20mL sterile plastic container. Approximately 2.5mL of this blood should be placed in a second fluoride/oxalate tube containing additional sodium fluoride (equivalent to 2% wv in 2.5mL) as a preservative.
Blood for qualitative analysis (screening) An additional larger specimen of blood (~ 20mL) for qualitative screening should be taken from the heart (preferably right atrium or inferior vena cava) or if necessary from another convenient large vessel. The site of collection must be indicated on the label. Container: This specimen should be placed in a plain 20 mL sterile plastic container.
Stomach tissue and contents may be useful in the investigation of oral cyanide poisoning, or in cases of rapid death where relatively large amounts of unabsorbed drug may be found in the stomach. In cases of suspected drug overdosage the entire stomach contents should be retained. If distinct tablets or capsules are observed in the stomach contents, these should be carefully extracted, and put in individual containers (e.g. plastic urine containers). Identification of such material can be carried out by reference to a computerised database of pharmaceutical products.
Liver tissue may be useful in certain complex poisoning cases. It is usual to take a portion of the right lobe of liver since it should be uncontaminated with bile and less affected by drug diffusion from the liver; 100 grams is sufficient for most analytical purposes.
Brain, A portion of about 100g brain should be taken; this may be useful in the investigation of death due to gases or volatile substances. Measurement of brain concentration of certain drugs may be helpful in certain cases e.g. cocaine deaths. The specimen should be placed in a glass specimen jar or nylon bag (volatile substance deaths) and deep-frozen prior to transport to the laboratory.
Lung A portion of about 100g lung from the apex should be taken. This may be useful in investigation of death due to gases or volatile substances. The specimen should be placed in a glass specimen jar or nylon bag and stored at 4oC prior to transport to the Laboratory. If death was possibly caused by the inhalation of hydrogen cyanide fumes, a lung should be sent intact, sealed in a nylon ( not polyvinylchloride ) bag11.
The Laboratory should be able to provide appropriate specimen containers for the collection of blood and urine specimens at post-mortem. Suitable packaging for sending specimens by post may also be supplied if required. All specimen bottles should be clearly labelled with the full name of the deceased, date of collection, and post-mortem or reference number. In the case of blood specimens, the specific site of sampling should always be given. All specimens should be stored at 4 oC before transporting them to the laboratory. Each specimen bottle should be securely sealed to prevent leakage, and individually packaged in separate plastic bags to ensure that there is no cross-contamination. Special care is required in the storage of specimens for the analysis of insulin, alcohols, cyanide and cocaine; also for volatile liquids or gases - please contact the Laboratory for guidance. It is important to get the samples to the laboratory as soon as possible (in terms of days ) to avoid the spurious formation of cyanide in stored blood samples. This usually occurs at room temperature so, if there is to be delay, refrigeration is essential. In contrast, some positive samples may actually decrease on storage, as described by Curry. Up to 70 per cent of the cyanide content may be lost after some weeks, from reaction with tissue components and conversion to thiocyanate11.
If cyanide victim death which have occurred in hospital, the hospital pathology laboratory should be contacted as soon as possible to see if any ante mortem specimens of urine, blood, serum, or plasma are available, and these should also be sent for analysis.
The usual blood, stomach contents, urine and any vomit should be submitted to the laboratory, taking particular care that the samples present no hazardto those packing, transporting or unpacking them. The labortory should be warned in advice that a possible cyanide case is coming their way.
1. Borron, Stephen W, MD, MS ; Toxicity, Cyanide, eMedicine, Article,Last update: February 12, 2003, www.emedicine.com/emerg/topic118.htm - 87k
eMedicine - Toxicity, Cyanide : Article by Stephen W Borron, MD, ...
2. RMIT University - Health and Safety Manual- ; Procedure for cyanide and poisoning treatment ; up date April 1998, Policy No.126.96.36.199
www.rmit.edu.au/ .../ - 39k -
RMIT - Cyanide Poisoning First Aid
3. BASKIN STEVEN I.,P HARM .D., P H .D., FCP, FACC, DABT, FATS*; AND THOMAS G. BREWER, MD, FACP, Cyanide Poisoning 271 Chapter 10, www.nbc-med.org/SiteContent/HomePage/whatsnew/ MedAspects/Ch-10electrv699.pdf [PDF]Chapter 10 CYANIDE POISONING
4. Bhattacharya,R; Antidotes to cyanide poisoning: Present status, Indian Journal of Pharmacology 2000;Educational forum, 32: 94-101
PDF]ANTIDOTES TO CYANIDE POISONING: PRESENT STATUS
Di Maio Dominick J. and Di Maio Vincent J.M; Deaths due to fire; Forensic Pathology;CRC Press,Inc;1993:13:327-345.
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Goodman and Gilman, Noxious gases and vapors; The Pharmacological Basis of Therapeutics; forth edition, the Macmillan company; 1955: 44 :934-936.
ATSDR - ToxFAQs: Cyanide www.atsdr.cdc.gov/tfacts8.html - 20k -
Huang, David T, MD; Cyanide, eMedicine, Article Last Updated July 31, 2002; www.emedicine.com/aaem/topic491.htm - 69k
eMedicine - Cyanide : Article by David T Huang, MD
10. Gonzales,T,A., Vance, M., Helpern, M., Umberger, C, J., Organic Poison: Volatile ;Legal Medicine Pathology and Toxicology, Appleeton Century Company Inc, 1954: 32 : 801-804..
11. Knight Bernard;
13. Sheehan, Simon Elliott, Dr. R.A. Braithwaite, Guide to Obtaining Specimens at Post-mortem for Analytical Toxicology, Last edited: January 15, 2002, http://www.toxlab.co.uk/postmort.htm